Molecular chaperones, such as Hsp70 and Hsp90, may help protect against neurodegenerative disorders, such as Alzheimer's and Huntington's diseases, which are caused by aberrant protein misfolding. However, a dearth of small molecule partners for the chaperones have limited our ability to probe their function in models of these diseases. The long-term goal of the Gestwicki laboratory is to uncover inhibitors and agonists of the chaperones to open new opportunities for exploration in this area. The objective of this particular proposal is to identify and characterize agonists of Hsp70 and use these to study the role of this chaperone in polyglutamine expansion (polyQ) models of Huntington's disease. Our central hypothesis is that direct stimulation of Hsp70 will provide relief from polyQ misfolding. In preliminary studies, we have uncovered small molecules that promote Hsp70's function and protect yeast and mammalian cell models of disease. Moreover, we have used these chemical probes to implicate Hsp70 as a crucial mediator of aggregation. Guided by this strong preliminary evidence, we propose three specific aims: (1) Identify additional small molecules that modify Hsp70's chaperone activity (2) Explore the interaction between these compounds and Hsp70 (3) Use these chemical tools to investigate how Hsp70 protects against polyQ self-assembly. This approach is innovative because other strategies have relied on initiation of the global cellular stress responses to modulate Hsp70 function. In contrast, our approach directly targets the chaperone without perturbing other cellular processes. This is significant because our chemical probes might allow us to, for the first time, identify Hsp70 as a drug target for neurodegenerative disorders and learn more about its role in disease. PUBLIC HEALTH RELEVANCE: Neurodegenerative disease is one of the greatest threats facing an aging population and the outlook for pharmaceutical intervention is uncertain. We have developed a new approach to discovery in this area by directly targeting molecular chaperones.